Maternal nutrient restriction during late gestation and early postnatal growth in sheep differentially reset the control of energy metabolism in the gastric mucosa.

Fetal growth restriction followed by accelerated postnatal growth contributes to impaired metabolic function in adulthood. The extent to which these outcomes may be mediated centrally within the hypothalamus, as opposed to in the periphery within the digestive tract, remains unknown. In a sheep model, we achieved intrauterine growth restriction experimentally by maternal nutrient restriction (R) that involved a 40% reduction in food intake through late gestation. R offspring were then either reared singly to accelerate postnatal growth (RA) or as twins and compared with controls also reared singly. From weaning, all offspring were maintained indoors until adulthood. A reduced litter size accelerated postnatal growth for only the first month of lactation. Independently from postnatal weight gain and later fat mass, R animals developed insulin resistance as adults. However, restricted accelerated offspring compared with both the control accelerated and restricted restricted offspring ate less and had higher fasting plasma leptin as adults, an adaptation which was accompanied by changes in energy sensing and cell proliferation within the abomasum. Additionally, although fetal restriction down-regulated gene expression of mammalian target of rapamycin and carnitine palmitoyltransferase 1-dependent pathways in the abomasum, RA offspring compensated for this by exhibiting greater activity of AMP-activated kinase-dependent pathways. This study demonstrates a role for perinatal nutrition in the peripheral control of food intake and in energy sensing in the gastric mucosal and emphasizes the importance of diet in early life in regulating energy metabolism during adulthood.

Nutritional regulation of fetal growth and implications for productive life in ruminants.

The maternal nutritional and metabolic environment is critical in determining not only the reproductive success but also the long-term health and viability of the offspring. Changes in maternal diet at defined stages of gestation coincident with different stages of development can have pronounced effects on organ and tissue function in later life. This includes adipose tissue for which differential effects are observed between brown and white adipose tissues. One early, critical window of organ development in the ruminant relates to the period covering uterine attachment, or implantation, and rapid placental growth. During this period, there is pronounced cell division within developing organelles in many fetal tissues, leading to their structural development. In sheep, a 50% global reduction in caloric intake over this specific period profoundly affects placental growth and morphology, resulting in reduced placentome weight. This occurs in conjunction with a lower capacity to inactivate maternal cortisol through the enzyme 11ß-hydroxysteroid dehydrogenase type 2 in response to a decrease in maternal plasma cortisol in early gestation. The birth weight of the offspring is, however, unaffected by this dietary manipulation and, although they possess more fat, this adaptation does not persist into adulthood when they become equally obese as those born to control fed mothers. Subsequently, after birth, further changes in fat development occur which impact on both glucocorticoid action and inflammatory responses. These adaptations can include changes in the relative populations of both brown and white adipocytes for which prolactin acting through its receptor appears to have a prominent role. Earlier when in utero nutrient restricted (i.e. between early-to-mid gestation) offspring are exposed to an obesogenic postnatal environment; they exhibit an exaggerated insulin response, which is accompanied by a range of amplified and thus, adverse, physiological or metabolic responses to obesity. These types of adaptations are in marked contrast to the effect of late gestational nutrient restriction, which results in reduced fat mass at birth. As young adults, however, fat mass is increased and, although basal insulin is unaffected, these offspring are insulin resistant. In conclusion, changes in nutrient supply to either the mother and/or her fetus can have profound effects on a range of metabolically important tissues. These have the potential to either exacerbate, or protect from, the adverse effects of later obesity and accompanying complications in the resulting offspring.

Influence of prenatal nutrition and obesity on tissue specific fat mass and obesity-associated (FTO) gene expression.

The recent discovery of an association between body composition, energy intake and the fat mass and obesity-associated (FTO) gene represents a promising new therapeutic target in obesity prevention. In a well, pre-established large animal model, we investigated the regulation of FTO gene expression under conditions either leading to obesity or increased risk of obesity related disorders: i) a sedentary 'Western' lifestyle and ii) prenatal exposure to nutrient restriction. Pregnant sheep were either fed to fully meet their nutritional requirements throughout gestation or 50% of this amount from early-to-mid gestation. Following weaning, offspring were either made obese through exposure to a sedentary obesogenic environment or remained lean. A significant positive relationship between placental FTO gene expression and fetal weight was found at 110 days gestation. In both the newborn and adult offspring, the hypothalamus was the major site of FTO gene expression. Hypothalamic FTO gene expression was upregulated by obesity and was further increased by prenatal nutrient restriction. Importantly, we found a strong negative relationship between the hypothalamic FTO gene expression and food intake in lean animals only that may imply FTO as a novel controller of energy intake. In contrast, FTO gene expression in the heart was downregulated in obese offspring born to nutrient restricted mothers. In addition, FTO gene expression was unaffected by obesity or prenatal diet in insulin-dependent tissues, where it changed with age possibly reflecting adaptations in cellular energetic activity. These findings extend information gained from human epidemiology and provide new insights into the regulation of in vivo energy metabolism to prevent obesity.

The differential effects of the timing of maternal nutrient restriction in the ovine placenta on glucocorticoid sensitivity, uncoupling protein 2, peroxisome proliferator-activated receptor-gamma and cell proliferation.

Nutrient restriction (NR) during critical windows of pregnancy has differential effects on placento-fetal growth and development. Our study, therefore, investigated developmental and metabolic adaptations within the ovine placenta following NR at different critical windows during the first 110 days of gestation (term=147 days). Thus, the effects of NR on cell proliferation, glucocorticoid sensitivity, IGF1 and 2 receptor, peroxisome proliferator-activated receptor gamma (PPARG), and uncoupling protein (UCP)2 gene expression in the placenta were examined. Singleton bearing sheep (n=4-8 per group) were fed either 100% of their total metabolizable energy requirements throughout the study or 50% of this amount between 0-30, 31-65, 66-110, and 0-110 days gestation. A significant reduction in cell proliferation and increased gene expression for the glucocorticoid and IGF2 receptors, PPARG, and UCP2 were detected in placentae sampled from mothers who were nutrient restricted between days 66 and 110 of gestation, only, relative to controls. This window of gestation coincides with the maximum placental growth and the start of exponential growth of the fetus when there are substantially increased metabolic demands on the placenta compared with earlier in gestation. Consequently, increased glucocorticoid sensitivity and suppressed IGF2 action could contribute to a switch in the placenta from proliferation to differentiation, thereby improving its nutrient transfer capacity. Upregulation of PPARG and UCP2 would promote placental fatty acid metabolism thereby limiting glucose utilization. These compensatory placental responses may serve to maintain fetal growth but could result in adverse adaptations such as the early onset of the metabolic syndrome in later life.

Effect of maternal nutrient restriction from early to midgestation on cardiac function and metabolism after adolescent-onset obesity.

Maternal nutrient restriction (NR) from early to midgestation has marked effects on endocrine sensitivity and organ function of the resulting offspring. We hypothesized that early NR may reset the expression profile of genes central to myocardial energy metabolism, influencing ectopic lipid deposition and cardiac function in the obese adult offspring. NR offspring were exposed to an "obesogenic" environment, and their cardiac function and molecular indexes of myocardial energy metabolism were assessed to explore the hypothesis that an obese individual's risk of heart disease may be modified after maternal NR. Pregnant sheep were fed 100% (control) or 50% (NR) energy requirement from days 30 to 80 of gestation and 100% energy requirement thereafter. At weaning, offspring were exposed to an obesogenic environment or remained lean. At approximately 1 yr of age, the hemodynamic response of these offspring to hypotension, together with left ventricular expression profiles of fatty acid-binding protein 3 (FABP3), peroxisome proliferator-activated receptor-gamma (PPARgamma) and its coactivator (PGC)-1alpha, acetyl-CoA carboxylase (ACC), AMP-activated protein kinase (AMPK)-alpha(2), and voltage-dependent anion channel 1 (VDAC1), was determined. Obesity produced left ventricular hypertrophy in all animals, with increased ectopic (myocardial) lipid in NR offspring. Obesity per se significantly reduced myocardial transcript expression of PGC-1alpha, AMPKalpha(2), VDAC1, and ACC and increased expression of PPARgamma and FABP3. However, although NR animals were similarly obese, their transcript expression of ACC, PPARgamma, and FABP3 was similar to that of lean animals, indicating altered cardiac energy metabolism. Indeed, blunted tachycardia and an amplified inotropic response to hypotension characterized cardiac function in obese NR offspring. The results suggest that maternal NR during early organogenesis can precipitate an altered myocardial response to hypotension and increased myocardial lipid deposition in the adult offspring after adolescent-onset obesity, potentially rendering these individuals more at risk of early heart failure as they age.

Maternal nutrient restriction between early and midgestation and its impact upon appetite regulation after juvenile obesity.

The impact of maternal nutrient restriction during early-to-midgestation, a period coinciding with early fetal brain development, on appetite regulation and energy balance in the offspring after juvenile obesity was examined. Pregnant sheep were either fed to meet fully their nutritional requirements throughout gestation or 50% of this amount between 30 and 80 d gestation. After weaning, offspring were either made obese through exposure to a sedentary obesogenic environment or remained lean. Maternal nutrient restriction had no effect on birth weight or subsequent growth. At 1 wk of age, only, gene expression for neuropeptide Y in the hypothalamus was reduced in nutrient-restricted offspring. By 1 yr of age, all O animals had increased plasma leptin, nonesterified fatty acids, and insulin, with the latter effect amplified in NR offspring. Fasting plasma glucose, triglycerides, and cortisol were unaffected by obesity. The entrained reduction in physical activity that led to obesity persisted when all animals were maintained within individual pens. However, NRO offspring exhibited reduced daily food intake and were, therefore, no longer in positive "energy balance." This adaptation was accompanied by elevated hypothalamic gene expression for the melanocortin-4 and insulin receptors, AMP-activated kinase, and acetyl coenzyme A carboxylase alpha. In conclusion, nutrient restriction specifically targeted over the period of early fetal brain development contributes to a profoundly different adaptation in energy balance after juvenile obesity. The extent to which this adaptive response may benefit the offspring or result in an exacerbated risk of type 2 diabetes remains to be established.

Childhood obesity and insulin resistance in a Yucatan mini-piglet model: putative roles of IGF-1 and muscle PPARs in adipose tissue activity and development.

OBJECTIVE: To explore metabolic and cellular modifications induced during childhood obesity, in a novel animal model of obese mini-piglets. DESIGN: A total of 10 four-month old Yucatan mini-pigs were followed from prepuberty to adulthood. Animals were divided into two groups. The first one had been overfed (OF) a western-type diet and the second one had been normally fed a control recommended human-type diet (NF). MEASUREMENTS: Plasma insulin-like growth factor 1 (IGF-1), insulin, leptin, nonesterified fatty acids, triglycerides (TGs) and glucose were determined at sexual maturity and at young adulthood. Quantitative gene expressions of peroxysome-proliferator-activated receptors (PPARs), glucose transporter 4, insulin receptor, IGF-1, leptin and interleukin-6 (IL-6) in skeletal muscle, adipose tissue and liver were also measured at both stages. Adult insulin sensitivity was measured via euglycaemic-hyperinsulinaemic clamps. RESULTS: Increased body weight in adult OF pigs was associated with increased body size and low insulin sensitivity. Sexually mature OF pigs had higher IGF-1 plasma concentrations than their lean littermates (P < 0.05). In the OF group, TGs and glucose were both decreased (P < 0.05). Muscle PPARgamma and alpha in OF pubescent pigs as compared to NF pigs were 11 times higher and 20 times lower, respectively (P < 0.01). CONCLUSION: Obesity and insulin resistance induced by overfeeding mini-pigs during development and puberty were not associated with the cluster of metabolic modifications frequently observed in their adult littermates. Increased IGF-1 concentrations and modifications of skeletal muscle PPAR (alpha and gamma) expressions may help the young obese pig to partially regulate its glycaemia and triglyceridaemia through an increase of fat mass, which maintains its high insulin sensitivity.